Abstract

OBJECTIVE/AIMS: To examine the pathophysiology of lipoatrophy in subcutaneous adipose tissue among Western Australian HIV cohort participants, focusing particularly on the potential role of nucleoside reverse transcriptase inhibitor (NRTI)-associated mitochondrial toxicity.

RESULTS: Compared with HIV+ ART-naïve controls (n=24, 1288 copies/cell), median mtDNA copies/cell was reduced by 81% in stavudine recipients (n=28, 240 copies/cell, P<0.0001) and by 44% in zidovudine recipients (n=29, 726 copies/cell, P=0.006). Regimens without stavudine/ zidovudine (n=11, 1514 copies/cell) had similar mtDNA levels to controls (P>0.5). Significant differences between stavudine/lamivudine (n=23) and zidovudine/lamivudine (n=28) regimens were also found (P=0.002). Commencing/switching NRTI therapy was associated with significant changes in mtDNA levels within 2–12 months in sequential biopsy samples (n=19, 38 biopsies, P<0.01). No association between mtDNA levels and use of HIV protease inhibitors was detected (P=0.6), and CD4 T cell counts at the time of biopsy were also similar between NRTI treatment groups (P=0.9). Adipose tissue toxicity correlated with mtDNA depletion and was characterized by adipocyte pleiomorphism and mitochondrial proliferation, progressing to adipocyte loss with marked macrophage infiltration and disordered tissue architecture. Lipid-laden macrophages were detected indicating adipocyte apoptosis. In 4/7 biopsies with <300 mtDNA copies/cell, relative depletion of mtDNA-encoded protein COX I was detected. No significant differences were noted between PI-treated and PI-naïve biopsy samples.

CONCLUSION/DISCUSSION: These data indicate that adipocyte mtDNA depletion and mitochondrial toxicity are prominent in subcutaneous fat samples obtained from NRTI-treated individuals, providing a pathophysiological basis for the observed effects of NRTI choice and duration on lipoatrophy risk.